Revision: Drug dependence is linked to diminished hippocampal structure and function, and the hippocampus is involved in drug reward and relapse to drug seeking. Thus, our understanding and treatment of addiction will be greatly improved if we can clarify the time course, extent, and cause of drug-induced hippocampal neuroadaptations and identify if and how hippocampal neuroadaptations impact addictive behaviors. A notable aspect of the hippocampus is its ability to generate new neurons throughout life. Adult-generated neurons are functionally integrated into hippocampal circuitry and are involved in some types of learning. Drugs of abuse, like morphine, decrease neurogenesis in the hippocampal dentate gyrus subgranular zone (SGZ), raising the possibility that opiate-induced alteration in neurogenesis leads to cognitive deficits, continued drug taking or relapse, or otherwise impedes recovery. The parent grant application, DA 016765, has three aims to test this possibility: Aim 1) Determine how morphine self-administration and withdrawal alter discrete stages of adult hippocampal neurogenesis. Aim 2) Assess how altered adult hippocampal neurogenesis relates to drug seeking. Aim 3) Evaluate the involvement of adult-generated hippocampal neurons in drug/context association. For this competitive revision, we propose a new aim to be completed in one year: Aim 4) Evaluate the involvement of adult-generated hippocampal neurogenesis in the vulnerability to morphine addiction. Based on our recent publication (Noonan et al., J Neuroscience, 2010), we hypothesize that ablation of adult neurogenesis via cranial radiation will enhance vulnerability to self-administration in an animal model of opiate addiction without disrupting response to non-drug rewards. The extensive analysis of behavior in this new aim will reveal how adult-generated neurons contribute to basal and reward-based behavior, and makes this aim perfectly-suited for consideration through the NIH Basic Behavioral and Social Sciences Opportunity Network. By providing insight into the relationship among adult neurogenesis, opiates, and behavior, these studies will provide much-needed information relevant to our understanding of the addicted and the non-addicted brain and may indicate novel avenues to treat and prevent addiction and improve brain health in general. PUBLIC HEALTH RELEVANCE: Drug addiction is a devastating disorder marked by compulsive drug use, high propensity to relapse to drug taking, and cognitive deficits. Drugs of abuse, including morphine, lead to a decrease in the number of new neurons in the hippocampus, a brain region important for learning and memory. We will explore the potentially reciprocal relationship between opiate addiction and adult hippocampal neurogenesis, thus providing much- needed insight into the structure and function of the addicted brain as well as the function of adult-generated neurons in the non-addicted brain.